Nicotinamide Adenine Dinucleotide (NAD+) is a biochemical found in all cells that was first characterized over 100 years ago due to its role in oxidoreductase reactions. Since then NAD+ and its related pyridine nucleotides NADH, NADP+, and NADPH are recognized as the major redox carriers in all organisms. These pyridine dinucleotides regulate the cytosolic and mitochondrial redox state and are key participants monitoring the metabolic status of the cell. This is because NAD+ and NADH act as hydride accepting and donating cofactors for metabolic enzymes involved in glycolysis, the TCA cycle, and the respiratory chain and thereby redistribute reducing equivalents generated from these catabolic processes into the de novo synthesis of new biomolecules. (Houtkooper et al Endo Reviews (2010) 31:194-223; Koch-Nolte et al (2009) Science Signaling 2:mr1; Houtkooper and Auwerx (2012) J. Cell Biol 199:205-209; Berger et al Trends in Bioch Sci 29:11-118)
In addition to its long recognized role as a cofactor for oxidoreductases, more recent research demonstrates that NAD+ is also a substrate for various enzymes, where it is consumed in the process of donating its ADP ribose to acceptor molecules. The enzymes that are the major consumers of NAD+ are the ADP ribosyl transferases (i.e. PARP and ART family of enzymes), the sirtuins (Sirt1-7), and the ADP ribosyl cyclases/hydrolases (CD38/CD157). These enzymes are involved in pathways that regulate Ca++ signaling, gene transcription, DNA repair, cell survival, energy metabolism, and oxidative stress. Thus, NAD+ and its phosphorylated relatives NADP and NAADP, both of which are derived from NAD+, also act as signaling molecules. NAD+ is also a key component of the circadian cycle with daily oscillations that tie cellular metabolism to chromatin remodeling and gene transcription. It is known that exercise and caloric restriction elevate NAD+ levels while aging and obesity decrease cellular NAD+ levels. Restoring NAD++ levels in disease states that consume significant amounts of NAD++ will likely have medical benefits as the cell strives to maintain its energy status during stress. (Tevy et al (2103) Trends in Endo and Metab 24:229-237; Pugh et al (2013) Aging Cell 12:672-681; Massudi et al PLoS ONE 7:e42357; Xu and Sauve (2010) Mech of Ageing and Development 131:287-298; Sassone-Corsi (2012) 153:1-5).
Cellular NAD+ is produced by either the de novo synthesis pathway from tryptophan or by a salvage synthesis pathway from precursors such as nicotinic acid (niacin) and nicotinamide, both of which are obtained from dietary sources. A third way to modulate cellular NAD+ levels is to block consumption of NAD+ by inhibiting enzymes that consume NAD+. CD38 is one such consumer of NAD+. Also known as ADP ribosyl cyclase, CD38 is a type II membrane-anchored enzyme. It efficiently catalyzes the breakdown of NAD+ to nicotinamide and ADPR and hydrolyzes NAADP to ADPRP. CD38 can also act as a cyclase converting NAD+ to cADPR, although it is 100-fold less efficient as a cyclase than as a hydrolase. CD38 was first characterized as a surface antigen on immune cells and is broadly distributed throughout most tissues in the body. It exists on the plasma membrane and on the membranes of intracellular organelles such as the nucleus and mitochondria. As predicted from its function as a NAD+ glycohydrolase, CD38 KO mice have elevated NAD+ levels relative to wild-type controls. Likewise, inhibitors of CD38 enzyme activity also modulate NAD+ tissue levels and would be useful in treating various diseases where CD38 is over expressed or where cellular NAD+ levels are depressed or desynchronized. (Malavasi et al (2008) 88:841-886)
There are many references suggesting the benefits of modulating NAD+ levels. Compounds which inhibit CD38, and thereby raise NAD+ levels may be useful in treating diseases or conditions indicated to benefit from NAD+. The following are examples, with references:                acute lung injury/ARDS, see, for example, Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion, Su, C1-5. F.; Liu, D. D.; Kao, S. J.; Chen, H. I. European Respiratory Journal (2007), 30(2), 199-204;        hyperphosphatemia, see for example, Nicotinamide suppresses hyperphosphatemia in hemodialysis patients, Takahashi, Yutaka; Tanaka, Araki; Nakamura, Tsukasa; Fukuwatari, Tsutomu; Shibata, Katsumi; Shimada, Noriaki; Ebihara, Isao; Koide, Hikaru, Kidney International (2004), 65(3), 1099-1104;        alcohol intolerance, see for example, Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase “Asian” variant, Larson, Heather N.; Weiner, Henry; Hurley, Thomas D. Journal of Biological Chemistry (2005), 280(34), 30550-30556;        lupus, see for example, CD38 polymorphisms in Spanish patients with systemic lupus erythematosus, Gonzalez-Escribano Maria Francisca; Aguilar Francisco; Torres Belen; Sanchez-Roman Julio; Nunez-Roldan Antonio Human immunology (2004), 65(6), 660-4, and Increased CD38 expression in T cells and circulating anti-CD38 IgG autoantibodies differentially correlate with distinct cytokine profiles and disease activity in systemic lupus erythematosus patients Pavon, Esther J.; Zumaquero, Esther; Rosal-Vela, Antonio; Khoo, Keng-Meng; Cerezo-Wallis, Daniela; Garcia-Rodriguez, Sonia; Carrascal, Montserrat; Abian, Joaquin; Graeff, Richard; Callejas-Rubio, Jose-Luis; et al Cytokine+ (2013), 62(2), 232-243;        rheumatoid arthritis, see, for example, Mice deficient in CD38 develop an attenuated form of collagen type Il-induced arthritis Postigo, Jorge; Iglesias, Marcos; Cerezo-Wallis, Daniela; Rosal-Vela, Antonio; Garcia-Rodriguez, Sonia; Zubiaur, Mercedes; Sancho, Jaime; Merino, Ramon; Merino, Jesus PLoS One (2012), 7(3), e33534;        ataxia-telangiectasia, see, for example, Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice Stern, Nora; Hochman, Ayala; Zemach, Naty; Weizman, Nir; Hammel, Ilan; Shiloh, Yosef; Rotman, Galit; Barzilai, An, Journal of Biological Chemistry (2002), 277(1), 602-608;        sleep disorders, see, for example, The effects of nicotinamide upon sleep in humans Robinson C R; Pegram G V; Hyde P R; Beaton J M; Smythies J R Biological psychiatry (1977)), 12(1), 139-43;        epilepsy, see, for example, Partial epilepsy with pericentral spikes: a new familial epilepsy syndrome with evidence for linkage to chromosome 4p15 Kinton Lucy; Johnson Michael R; Smith Shelagh J M; Farrell Fiona; Stevens John; Rance James B; Claudino Angelica M; Duncan John S; Davis Mary B; Wood Nicholas W; et al Annals of neurology (2002), 51(6), 740-9;        exercise intolerance, see, for example, Effects of exercise on oxidative activities in rat liver mitochondria, Glick, J. Leslie American Journal of Physiology (1966), 210(6), 1215-21;        small lung cell carcinoma, see, for example, β-Lapachone Micellar Nanotherapeutics for Non-Small Cell Lung Cancer Therapy, Blanco, Elvin; Bey, Erik A.; Khemtong, Chalermchai; Yang, Su-Geun; Setti-Guthi, Jagadeesh; Chen, Huabing; Kessinger, Chase W.; Carnevale, Kevin A.; Bornmann, William G.; Boothman, David A.; et al Cancer Research (2010), 70(10), 3896-3904;        renal clear cell carcinoma, see, for example, Identification of nicotinamide N-methyltransferase as a novel tumor marker for renal clear cell carcinoma Sartini, Davide; Muzzonigro, Giovanni; Milanese, Giulio; Pierella, Francesca; Rossi, Valentina; Emanuelli, Monica Journal of Urology (New York, N.Y., United States) (2006), 176(5), 2248-2254;        hypertension, see, for example, Mice lacking the ADP ribosyl cyclase CD38 exhibit attenuated renal vasoconstriction to angiotensin II, endothelin-1, and norepinephrine Thai Tiffany L; Arendshorst William J American journal of physiology. Renal physiology (2009), 297(1), F169-76;        hypoxic pulmonary vasoconstriction, see, for example, Adp-ribosyl cyclase and cyclic ADP-ribose hydrolase act as a redox sensor. a primary role for cyclic ADP-ribose in hypoxic pulmonary vasoconstriction, Wilson H L; Dipp M; Thomas J M; Lad C; Galione A; Evans A M The Journal of biological chemistry (2001), 276(14), 11180-8;        hansen's disease, see, for example, Nicotinamide adenine dinucleotide glycohydrolase in normal and leprous armadillos Dhople, Arvind M.; Johnson, Kara J.; Williams, Sharon L.; Zeigler, Joseph A.; Cook, Camille A.; Storrs, Eleanor E. Microbios Letters (1985), 28(109), 17-20;        tuberculosis, see, for example, NAD+ auxotrophy is bactericidal for the tubercle bacilli, Vilcheze, Catherine; Weinrick, Brian; Wong, Ka-Wing; Chen, Bing; Jacobs, William R., Jr. Molecular Microbiology (2010), 76(2), 365-377;        leishmaniasis, see, for example, The NAD+ metabolism of Leishmania, notably the enzyme nicotinamidase involved in NAD+ salvage, offers prospects for development of anti-parasite chemotherapy Michels Paul A M; Avilan Luisana Molecular microbiology (2011), 82(1), 4-8;        cardiac hypertrophy/CHF, see, for example, Exogenous NAD+ Blocks Cardiac Hypertrophic Response via Activation of the SIRT3-LKB1-AMP-activated Kinase Pathway Pillai, Vinodkumar B.; Sundaresan, Nagalingam R.; Kim, Gene; Gupta, Madhu; Rajamohan, Senthilkumar B.; Pillai, Jyothish B.; Samant, Sadhana; Ravindra, P. V.; Isbatan, Ayman; Gupta, Mahesh P., Journal of Biological Chemistry (2010), 285(5), 3133-3144;        muscular dystrophy, see, for example, NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy, Goody, Michelle F.; Kelly, Meghan W.; Reynolds, Christine J.; Khalil, Andre; Crawford, Bryan D.; Henry, Clarissa A. PLoS Biology (2012), 10(10), e1001409;        stroke, see, for example, CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia, Choe, Chi-un; Lardong, Kerstin; Gelderblom, Mathias; Ludewig, Peter; Leypoldt, Frank; Koch-Nolte, Friedrich; Gerloff, Christian; Magnus, Tim PLoS One (2011), 6(5), e19046;        organ reperfusion injury, see, for example, Mouse embryonic fibroblasts from CD38 knockout mice are resistant to oxidative stresses through inhibition of reactive oxygen species production and Ca2+ overload Ge, Yan; Jiang, Wei; Gan, Lu; Wang, Li-Jun; Sun, Chang-Yan; Ni, Pei-Yan; Liu, Yin; Wu, Si-Si; Gu, Lun-Da; Zheng, Wei; et al Biochemical and Biophysical Research Communications (2010), 399(2), 167-172;        idiopathic pulmonary fibrosis, see, for example, Biochemical mechanisms for the attenuation of bleomycin-induced lung fibrosis by treatment with niacin in hamsters: the role of NAD+ and ATP O'Neill, Charles A.; Giri, Shri N. Experimental Lung Research (1994), 20(1), 41-56;        pancreatitis, see, for example, The Renin-Angiotensin System and Reactive Oxygen Species: Implications in Pancreatitis Chan, Yuk Cheung; Leung, Po Sing Antioxidants & Redox Signaling (2011), 15(10), 2743-2755;        cystic fibrosis, see, for example, Metabolomic Profiling Reveals Biochemical Pathways and Biomarkers Associated with Pathogenesis in Cystic Fibrosis Cells Wetmore, Diana R.; Joseloff, Elizabeth; Pilewski, Joseph; Lee, Douglas P.; Lawton, Kay A.; Mitchell, Matthew W.; Milburn, Michael V.; Ryals, John A.; Guo, Lining, Journal of Biological Chemistry (2010), 285(40), 30516-30522;        asthma, see, for example, Role of CD38 in airway function, Kang, Bit Na; Guedes, Alonso G. P.; Tirumurugaan, K. G.; Jude, Joseph A.; Deshpande, Deepak A.; Panettieri, Reynold A.; Amrani, Yassine; Lund, Frances E.; Walseth, Timothy F.; Kannan, Mathur S. Current Respiratory Medicine Reviews (2006), 2(2), 143-156;        COPD, see, for example, Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients, Hageman, Geja J.; Lark, Ingrid; Pennings, Herman-Jan; Haenen, Guido R. M. M.; Wouters, Emiel F. M.; Bast, Aalt Free Radical Biology & Medicine (2003), 35(2), 140-148;        Irritable Bowel Syndrome/Colitis, see, for example, Adenosine 5′-diphosphate-ribose is a neural regulator in primate and murine large intestine along with β-NAD+ Durnin, Leonie; Hwang, Sung Jin; Ward, Sean M.; Sanders, Kenton M.; Mutafova-Yambolieva, Violeta N. Journal of Physiology (Oxford, United Kingdom) (2012), 590(8), 1921-1941;        gout, see, for example, Genome-wide scan identifies a quantitative trait locus at 4p15.3 for serum urate, Cummings Nik; Dyer Thomas D; Kotea Navaratnam; Kowlessur Sudhir; Chitson Pierrot; Zimmet Paul; Blangero John; Jowett Jeremy B M European journal of human genetics: EJHG (2010), 18(11), 1243-7;        obesity/sarcopenic obesity, see, for example, The enzyme CD38 (a NAD+ glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity Barbosa Maria Thereza P; Soares Sandra M; Novak Colleen M; Sinclair David; Levine James A; Aksoy Pinar; Chini Eduardo Nunes, FASEB journal: official publication of the Federation of American Societies for Experimental Biology (2007), 21(13), 3629-39;        Metabolic Syndrome, see, for example, Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome, Escande Carlos; Nin Veronica; Price Nathan L; Capellini Verena; Gomes Ana P; Barbosa Maria Thereza; O'Neil Luke; White Thomas A; Sinclair David A; Chini Eduardo N Diabetes (2013), 62(4), 1084-93;        end stage renal disease, see, for example, A genome scan for all-cause end-stage renal disease in African Americans, Freedman, Barry I.; Bowden, Donald W.; Rich, Stephen S.; Valis, Christopher J.; Sale, Michele M.; Hicks, Pamela J.; Langefeld, Carl D. Nephrology, Dialysis, Transplantation (2005), 20(4), 712-718;        dyslipidemia, see, for example, A genome-wide screen for interactions reveals a new locus on 4p15 modifying the effect of waist-to-hip ratio on total cholesterol, Surakka Ida; Isaacs Aaron; Karssen Lennart C; Laurila Pirkka-Pekka P; Middelberg Rita P S; Tikkanen Emmi; Ried Janina S; Lamina Claudia; Mangino Massimo; Igl Wilmar; et al PLoS genetics (2011), 7(10), e1002333;        hearing loss, see, for example, Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction Someya, Shinichi; Yu, Wei; Hallows, William C.; Xu, Jinze; Vann, James M.; Leeuwenburgh, Christiaan; Tanokura, Masaru; Denu, John M.; Prolla, Tomas A. Cell (Cambridge, Mass., United States) (2010), 143(5), 802-812;        steatosis/NASH, see, for example, Elevated microRNA-34a in obesity reduces NAD+(+) levels and SIRT1 activity by directly targeting NAMPT Choi Sung-E; Fu Ting; Seok Sunmi; Kim Dong-Hyun; Yu Eunkyung; Lee Kwan-Woo; Kang Yup; Li Xiaoling; Kemper Byron; Kemper Jongsook Kim Aging cell (2013);        Alzheimer's disease, see, for example, Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models Gong Bing; Pan Yong; Vempati Prashant; Zhao Wei; Knable Lindsay; Ho Lap; Wang Jun; Sastre Magdalena; Ono Kenjiro; Sauve Anthony A; et al Neurobiology of aging (2013), 34(6), 1581-8;        multiple sclerosis, see, for example, The importance of NAD+ in multiple sclerosis, Penberthy, W. Todd; Tsunoda, Ikuo Current Pharmaceutical Design (2009), 15(1), 64-99;        neurocognitive disorders, see, for example, CD38/cyclic ADP-ribose regulates astrocyte calcium signaling: implications for neuroinflammation and HIV-1-associated dementia Banerjee Sugato; Walseth Timothy F; Borgmann Kathleen; Wu Li; Bidasee Keshore R; Kannan Mathur S; Ghorpade Anuja Journal of neuroimmune pharmacology: The official journal of the Society on NeuroImmune Pharmacology (2008), 3(3), 154-64;        optic neuropathy, see, for example, Axonal and cell body protection by nicotinamide adenine dinucleotide in tumor necrosis factor-induced optic neuropathy Kitaoka, Yasushi; Hayashi, Yasuhiro; Kumai, Toshio; Takeda, Hiroyuki; Munemasa, Yasunari; Fujino, Hiromi; Kitaoka, Yuka; Ueno, Satoki; Sadun, Alfredo A.; Lam, Tim T. Journal of Neuropathology & Experimental Neurology (2009), 68(8), 915-927;        postmenopausal osteoporosis, see, for example, CD38 is associated with premenopausal and postmenopausal bone mineral density and postmenopausal bone loss Drummond Frances J; Mackrill John J; O'sullivan Kathleen; Daly Mary; Shanahan Fergus; Molloy Michael G Journal of bone and mineral metabolism (2006), 24(1), 28-35;        Bipolar disorder/Schizophrenia, see, for example, Association analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia, Christoforou, A.; Le Hellard, S.; Thomson, P. A.; Morris, S. W.; Tenesa, A.; Pickard, B. S.; Wray, N. R.; Muir, W. J.; Blackwood, D. H.; Porteous, D. J.; Molecular Psychiatry (2007), 12(11), 1011-1025;        Huntington's disease, see, for example, The gene coding for PGC-1alpha modifies age at onset in Huntington's Disease, Weydt Patrick; Soyal Selma M; Gellera Cinzia; Didonato Stefano; Weidinger Claus; Oberkofler Hannes; Landwehrmeyer G Bernhard; Patsch Wolfgang Molecular neurodegeneration (2009), 4, 3;        diabetes, see, for example, Evidence of a novel quantitative-trait locus for obesity on chromosome 4p in mexican Americans Arya, Rector; Duggirala, Ravindranath; Jenkinson, Christopher P.; Almasy, Laura; Blangero, John; O'Connell, Peter; Stern, Michael P. American Journal of Human Genetics (2004), 74(2), 272-282;        Hartnup disease, see, for example, Hartnup disease Jepson, John B.; Spiro, Mary Jane, Metabolic Basis of Inherited Disease (1960), 1338-64;        Pellagra, see, for example, Pellagra: A clue as to why energy failure causes diseases? Williams, Adrian C.; Ramsden, David B. Medical Hypotheses (2007), 69(3), 618-628;        skin hyperpigmentation, see, for example, Oxidation of reduced nicotinamide adenine dinucleotide by melanin, Van Woert M H Life sciences (1967), 6(24), 2605-12;        diabetic neuropathy, see, for example, Functional and biochemical evidence indicating beneficial effect of Melatonin and Nicotinamide alone and in combination in experimental diabetic neuropathy, Negi Geeta; Kumar Ashutosh; Kaundal Ravinder K; Gulati Anil; Sharma Shyam S, Neuropharmacology (2010), 58(3), 585-92;        radiation protection, see, for example, NAD+ administration significantly attenuates synchrotron radiation X-ray-induced DNA damage and structural alterations of rodent testes Sheng, Caibin; Chen, Heyu; Wang, Ban; Liu, Tengyuan; Hong, Yunyi; Shao, Jiaxiang; He, Xin; Ma, Yingxin; Nie, Hui; Liu, Na; et al International Journal of Physiology, Pathophysiology and Pharmacology (2012), 4(1), 1-9;        UV skin damage, see, for example, NAD in skin: therapeutic approaches for niacin Benavente, Claudia A.; Jacobson, Myron K.; Jacobson, Elaine L. Current Pharmaceutical Design (2009), 15(1), 29-38;        psoriasis, see, for example, In search for new antipsoriatic agents: NAD+ topical composition, Wozniacka A; Szajerski P; Adamus J; Gebicki J; Sysa-Jedrzejowska A Skin pharmacology and physiology (2007), 20(1), 37-42;        periodontal disease, see, for example, CD38 expression in neutrophils from patients with localized aggressive periodontitis, Fujita Tsuyoshi; Kantarci Alpdogan; Warbington Martha L; Zawawi Khalid H; Hasturk Hatice; Kurihara Hidemi; Van Dyke Thomas E Journal of periodontology (2005), 76(11), 1960-5;        chronic lymphocytic leukemia, see, for example, CD38 as a molecular compass guiding topographical decisions of chronic lymphocytic leukemia cells, Deaglio, Silvia; Vaisitti, Tiziana; Zucchetto, Antonella; Gattei, Valter; Malavasi, Fabio Seminars in Cancer Biology (2010), 20(6), 416-423;        amyelotrophic lateral sclerosis, see, for example, Biochemical alterations associated with ALS, Lawton, Kay A.; Cudkowicz, Merit E.; Brown, Meredith V.; Alexander, Danny; Caffrey, Rebecca; Wulff, Jacob E.; Bowser, Robert; Lawson, Robert; Jaffa, Matt; Milburn, Michael V.; et al Amyotrophic Lateral Sclerosis (2012), 13(1), 110-118;        Parkinson's disease, see, for example, Nicotinamide-N-methyltransferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson's disease, Aoyama K; Matsubara K; Kondo M; Murakawa Y; Suno M; Yamashita K; Yamaguchi S; Kobayashi S Neuroscience letters (2001), 298(1), 78-80;        Leber's hereditary amaurosis, see, for example, Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration Koenekoop, Robert K.; Wang, Hui; Majewski, Jacek; Wang, Xia; Lopez, Irma; Ren, Huanan; Chen, Yiyun; Li, Yumei; Fishman, Gerald A.; Genead, Mohammed; et al., Nature Genetics (2012), 44(9), 1035-1039;        insulin resistance, see, for example, Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice, Yoshino, Jun; Mills, Kathryn F.; Yoon, Myeong Jin; Imai, Shin-ichiro, Cell Metabolism (2011), 14(4), 528-536;        type I diabetes, see, for example, The use of nicotinamide in the prevention of type 1 diabetes, Elliott, R. B.; Pilcher, C. C.; Stewart, A.; Fergusson, D.; McGregor, M. A. Annals of the New York Academy of Sciences (1993), 696 (Immunosuppressive and Antiinflammatory Drugs), 333-41.        